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| Home > Articles > Published articles > Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance |
| Home > Articles > Published articles > Identification of a Molecularly-Defined Subset of Breast and Ovarian Cancer Models that Respond to WEE1 or ATR Inhibition, Overcoming PARP Inhibitor Resistance |
(Vall d'Hebron Institut d'Oncologia) (AstraZeneca Oncology R&D) (Vall d'Hebron Institut d'Oncologia) (AstraZeneca Oncology R&D) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (Vall d'Hebron Institut d'Oncologia) (The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre) (The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre) (The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (Cambridge Institute, Cancer research UK) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (Cambridge Institute, Cancer research UK) (The University of Texas) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (AstraZeneca Oncology R&D) (The CRUK Gene Function Laboratory and Breast Cancer Now Toby Robins Research Centre) (Vall d'Hebron Institut d'Oncologia) (Vall d'Hebron Institut d'Oncologia) (AstraZeneca Oncology R&D)| Date: | 2022 |
| Abstract: | PARP inhibitors (PARPi) induce synthetic lethality in homologous recombination repair (HRR)-deficient tumors and are used to treat breast, ovarian, pancreatic, and prostate cancers. Multiple PARPi resistance mechanisms exist, most resulting in restoration of HRR and protection of stalled replication forks. ATR inhibition was highlighted as a unique approach to reverse both aspects of resistance. Recently, however, a PARPi/WEE1 inhibitor (WEE1i) combination demonstrated enhanced antitumor activity associated with the induction of replication stress, suggesting another approach to tackling PARPi resistance. We analyzed breast and ovarian patientderived xenoimplant models resistant to PARPi to quantify WEE1i and ATR inhibitor (ATRi) responses as single agents and in combination with PARPi. Biomarker analysis was conducted at the genetic and protein level. Metabolite analysis by mass spectrometry and nucleoside rescue experiments ex vivo were also conducted in patient-derived models. Although WEE1i response was linked to markers of replication stress, including STK11/RB1 and phospho-RPA, ATRi response associated with ATM mutation. When combined with olaparib, WEE1i could be differentiated from the ATRi/olaparib combination, providing distinct therapeutic strategies to overcome PARPi resistance by targeting the replication stress response. Mechanistically, WEE1i sensitivity was associated with shortage of the dNTP pool and a concomitant increase in replication stress. Targeting the replication stress response is a valid therapeutic option to overcome PARPi resistance including tumors without an underlying HRR deficiency. These preclinical insights are now being tested in several clinical trials where the PARPi is administered with either the WEE1i or the ATRi. |
| Grants: | Instituto de Salud Carlos III PI17/01080 Ministerio de Economía y Competitividad PI12/02606 Ministerio de Economía y Competitividad AC15/00063 Ministerio de Economía y Competitividad AC15/00062 Ministerio de Economía y Competitividad CB16/12/00449 Instituto de Salud Carlos III PI19/01181 |
| Rights: | Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, i la comunicació pública de l'obra, sempre que no sigui amb finalitats comercials, i sempre que es reconegui l'autoria de l'obra original. No es permet la creació d'obres derivades.  |
| Language: | Anglès |
| Document: | Article ; recerca ; Versió publicada |
| Published in: | Clinical cancer research, Vol. 28 Núm. 20 (15 2022) , p. 4536-4550, ISSN 1557-3265 |
